Heritability And Genome-wide Association Study Of Serum Creatinine In Middle-aged And Older Twins

Background:Kidney is an important human organ with multiple functions such as regulating the acid-base balance of the human body.The decline of renal function is caused by both genetic and environmental factors,which have an important impact on personal health.Serum creatinine concentration is an indicator used in clinical practice to evaluate renal function widely.At present,several studies in China and abroad have explored the relationship between genetic factors and serum creatinine level,but there is a lack of research on Asian population.Therefore,in this study,the adult twins in Qingdao were investigated to explore the extent of genetic factors affecting serum creatinine and the relationship between specific gene loci and serum creatinine,providing some understanding for exploring the effects of genetic factors on renal function.Methods:The subjects were from Qingdao Twin Registration System.According to certain inclusion and exclusion criteria,the twins who meet the requirements were selected.Basic information such as sex and age were obtained through a questionnaire survey,while height and weight were measured during a physical examination.Serum creatinine levels and other information were obtained through laboratory testing.The zygosity of the twins was determined by sex,blood type and microsatellite DNA gene scanning and typing technology,and a structural equation model was constructed by Mx software to calculate the heritability.The adjusted covariates were age,sex,and body mass index.For untyped single nucleotide polymorphisms（SNPs）,the IMPUTE2software was used for imputation,while a genome-wide efficient mixed model association（GEMMA）was used for SNP-based analysis.A gene-based analysis was conducted using VEGAS2 software,while pathway analysis was performed using PASCAL software.Finally,the candidate genes obtained from the genome-wide association analysis were subjected to gene ontology（GO）enrichment analysis using Omic Share Tools（https://www.omicshare.com/tools/）.Results:A total of 374 pairs of twins were finally included in this study,of which 139pairs were dizygotic twins.The sample age ranged from 40 to 80 years old,and the serum creatinine level ranged from 10 to 126μmol/L.（1）In the results of heritability analysis,the correlation coefficient within the monozygotic twin group was less than 2 times of the correlation coefficient within the dizygotic twin group,and the ACE model was fitted.There was a significant difference between the whole model and its nested model.Combined with Akaike’s information criterion（AIC）,ACE model was the best fitting model,with additive genetic effects accounting for 35.44%and common environmental effects accounting for 52.13%.（2）According to SNP-based analysis,there was no population stratification,with7,217,494 SNPs in analysis.Among them,151 SNPs such as rs2313476,rs4395499,rs2399031,rs117877635,rs17470149,rs3746609,rs1400649,rs1607182,rs75495780and rs4614682 exceeded the recommended association level(P<1×10^-5).The rs2313476locus(P=1.80×10^-8)exceeded the significant association level(P<5×10^-8).（3）In the gene-based analysis,214 genes reached the recommend association level（P<0.05）,including PDCD6IPP2,ZNF671,SEC22A,HCG4B,BMP2K,OR52D1,PSMA4,KIAA0319,PNPLA3,and CLPX etc.The most significant correlation was found between PDCD6IPP2(P=1.19×10^-4)and serum creatinine level.Among them,the IL16gene was consistent with the results of SNP-based analysis.（4）Pathway-based analysis showed that 787 biological pathways were significantly correlated with serum creatinine（P<0.05）,including chemokine signaling pathway,extracellular matrix receptor interaction signaling pathway,glycolysis gluconeogenesis signaling pathway,cell adhesion molecule signaling pathway,glycosphingolipid biosynthesis ganglion series signaling pathway,glucagon-like peptide 1 regulatory signaling pathway for insulin secretion,intercellular communication signaling pathway,FGFR1 mutant signaling pathway,non-coding ribonucleic acid metabolic signaling pathway,tight junction interaction signaling pathway,interleukin signaling pathway and so on.（5）GO enrichment analysis showed that the biological functional items enriched with candidate genes in the peak region of genome-wide association analysis were methylated histone binding,positive regulation of histone H3-K27 methylation,regulation of histone H3-K27 methylation,extracellular regulation of signal transduction,toxin catabolic process,etc.Conclusion:The serum creatinine of Qingdao twin population was found to be of moderate genetic level,and 151 SNPs loci exceeding the recommended association level,214 genes reaching the recommended association level,and 787 significantly related biological pathways were found in this study,which will provide some references for exploring the effects of genetic factors on renal function in the future.